It is estimated that creatine transporter deficiency (CTD) causes between 1 and 5 percent of all X-linked mental retardation. The primary clinical manifestations of the affected males are mental retardation, severe expressive language disorder and a seizure disorder, requiring dependent care for life. Creatine transporter knockout mice were treated with LUM-001, a repurposed small molecule that was shown to be capable of (1) getting across the blood-brain barrier and (2) improving brain metabolism and cognitive function of the mice. LUM-001, which has an inactive Investigational New Drug (IND) application filed for another indication, was shown to be effective in treating and reversing CTD in the knockout mouse model. Two parallel groups of patients with brain creatine deficiency syndromes (GAMT and AGAT), which have similar clinical manifestations as CTD, show significant clinical improvement when supplemented with creatine monohydrate. Creatine monohydrate supplementation is not effective in CTD because the creatine transporter gene is defective, preventing creatine from crossing the blood-brain barrier. As a result, no clinical improvement has been measured in CTD patients when supplemented with creatine monohydrate. LUM-001 has been shown to cross the blood-brain barrier, interact with creatine kinase in the brain, become phosphorylated and act in the same way as creatine as an energy source. After TRNDs acceptance of the project, Lumos was able to secure additional funding from the Wellcome Trust and venture capital firms to speed the teams collaborative work. TRND scientists performed pharmacokinetic/distribution studies in animal models of the disease to better understand brain uptake of LUM-001. An in vitro disease model was developed - using patient skin cells - to study LUM-001 uptake and effect on metabolism. Toxicology studies, formulation development, and chemistry and manufacturing were completed to support an IND application and initiation of a Phase 1 clinical safety study in healthy volunteers. TRND is collaborating on a prospective natural history study of the disease course in patients at multiple sites, including the NIH Clinical Center, which was initiated in 2017 and is currently on-going.